Compactable oral formulations of ibutamoren

Abstract

The present disclosure relates to pharmaceutical solid forms and pharmaceutical compositions comprising ibutamoren or a pharmaceutically acceptable salt thereof, and methods for administering to a pediatric subject for treating growth hormone deficiency.

What is claimed is: 
     
       1. A compressed tablet comprising:
 (a) a plurality of roller-compacted drug-containing granules, the roller-compacted drug-containing granules comprising ibutamoren or a pharmaceutically acceptable salt thereof and intragranular excipients, wherein the ibutamoren or a pharmaceutically acceptable salt thereof is in an amount greater than or equal to 50% by weight of the tablet, and wherein the intragranular excipients comprise a binder selected from the group consisting of corn starch, pregelatinized starch, gelatin, polyvinyl alcohol, waxes, acacia sodium alginate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, microcrystalline cellulose, ethyl cellulose, hydroxyethyl cellulose, and combinations thereof in an amount ranging from about 2% w/w to about 60% w/w, a bulking agent in an amount ranging from about 1% w/w to about 40% w/w, a intragranular disintegrant comprising croscarmellose sodium, crospovidone, sodium starch glycolate, or combinations thereof in an amount ranging from about 1% w/w to about 5% w/w, and a intragranular lubricant in an amount ranging from about 0.5% w/w to about 2% w/w; and 
 (b) extragranular excipients, 
 wherein the tablet weighs less than about 20 mg and has a diameter of less than about 5 mm; and 
 wherein the tablet has a hardness greater than 0.7 Kp and a friability less than 1%. 
 
     
     
       2. The compressed tablet of  claim 1 , wherein the ibutamoren or a pharmaceutically acceptable salt thereof is in an amount from about 50% to about 90% by weight of the compressed tablet. 
     
     
       3. The compressed tablet of  claim 1 , wherein the ibutamoren or a pharmaceutically acceptable salt thereof is in an amount from 60% to about 80% by weight of the compressed tablet. 
     
     
       4. The compressed tablet of  claim 1 , wherein the pharmaceutically acceptable salt is ibutamoren mesylate. 
     
     
       5. The compressed tablet of  claim 1 , wherein the binder is in an amount ranging from about 2% w/w to about 30% w/w, the bulking agent is in an amount ranging from about 1% w/w to about 20% w/w, the intragranular disintegrant is in an amount ranging from about 1% w/w to about 5% w/w, and the intragranular lubricant is in an amount ranging from about 0.5% w/w to about 2% w/w. 
     
     
       6. The compressed tablet of  claim 1 , wherein the bulking agent is a sugar alcohol selected from the group consisting of xylitol, mannitol, sorbitol, erythritol, lactitol, pentitol, and hexitol. 
     
     
       7. The compressed tablet of  claim 6 , wherein the intragranular lubricant is magnesium stearate, calcium stearate, colloidal silica, talc, or combinations thereof. 
     
     
       8. The compressed tablet of  claim 1 , wherein the extragranular excipients comprise a extragranular disintegrant and a extragranular lubricant. 
     
     
       9. The compressed tablet of  claim 8 , wherein the extragranular disintegrant is in an amount ranging from about 1% w/w to about 5% w/w and the extragranular lubricant is in an amount ranging from about 0.5% w/w to about 5% w/w. 
     
     
       10. The compressed tablet of  claim 8 , wherein the extragranular lubricant is magnesium stearate, calcium stearate, colloidal silica, talc, or combinations thereof and the extragranular disintegrant is carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, sodium starch glycolate, low substituted hydroxypropyl cellulose, or combinations thereof. 
     
     
       11. The compressed tablet of  claim 1 , wherein the drug-containing granules have a bulk density less than 0.6 g/cc and/or a tapped density less than 0.78 g/cc. 
     
     
       12. The compressed tablet of  claim 1 , wherein the drug-containing granules have a D50 greater than about 175 μm. 
     
     
       13. The compressed tablet of  claim 1 , wherein the drug-containing granules have a D50 greater than about 400 μm. 
     
     
       14. The compressed tablet of  claim 1 , wherein the tablet has a diameter of less than about 4 mm, or less than about 3 mm. 
     
     
       15. The compressed tablet of  claim 1 , wherein the tablet has a diameter of less than about 4 mm. 
     
     
       16. The compressed tablet of  claim 1 , wherein the hardness is from about 1.5 Kp to about 6 Kp, when compressed using a 2.5 mm tablet tooling size. 
     
     
       17. The compressed tablet of  claim 1 , wherein the tablet is a coated tablet. 
     
     
       18. The compressed tablet of  claim 17 , wherein the coated tablet comprises one or more coating layers. 
     
     
       19. The compressed tablet of  claim 18 , wherein the one or more coating layers comprise a N,N-dimethylaminoethyl methacrylate/methacrylate/butylmethacrylate copolymer or a polyvinyl alcohol (PVA)-based coating free of polyethylene glycol. 
     
     
       20. The compressed tablet of  claim 18 , wherein the one or more coating layers provide a weight gain of about 5% to about 25% by weight based on the total weight of the tablet. 
     
     
       21. The compressed tablet of  claim 18 , wherein the one or more coating layers provide a weight gain of about 8% to about 20% by weight based on the total weight of the tablet. 
     
     
       22. A pharmaceutical composition comprising more than one compressed tablet of  claim 1 . 
     
     
       23. The pharmaceutical composition of  claim 22 , wherein the composition is in the form of a capsule containing 2-12 of the compressed tablets. 
     
     
       24. The pharmaceutical composition of  claim 23 , wherein the composition is in the form of a capsule containing 3, 4, or 12 of the compressed tablets. 
     
     
       25. The pharmaceutical composition of  claim 23 , wherein the capsule is a hard gelatin or hydroxypropyl methylcellulose (HPMC) capsule. 
     
     
       26. The pharmaceutical composition of  claim 22 , wherein the ibutamoren or a pharmaceutically acceptable salt thereof is in an amount from 50% to about 90% by weight of each compressed tablet. 
     
     
       27. A method of treating growth hormone deficiency, comprising administering to a pediatric patient in need thereof the compressed tablet of  claim 1 .